This University of Colorado Cancer Center proposes to continue its Specialized Program of Research Excellence (SPORE) in Lung Cancer to expand our understanding of the biology of lung cancer, to find new methods of diagnosis, prevention and treatment and to serve as a regional, national and international resource for the study of lung cancer. During the initial 2 1/2 years of our SPORE program, we were able to translate many basic science observations into relevant clinical studies. With respect to early detection, we: 1) collected more than 900 sputum samples from high- risk individuals and shoed that 27% of these had moderate dysplasia ro higher grade change and have accessioned these patients for continued observation; 2) accessioned more than 200 lung cancer specimens of all histologic types with matching pre and post surgical sputum samples for genetic testing of genes on chromosome 3p, 9p, 11q, and 17p; 3) showed that 3p genetic losses are among the first to occur in dysplasia; 4) developed FISH probes for evaluating 3p changes; 5) showed that pulmonary peptide production is an indicator of susceptibility to lung cancer, 6) showed that a fluorescent bronchoscope can detect regions of dysplasia in the bronchial epithelium, and 7) established a familial lung cancer clinic. With respect to prevention, we: 1) instituted a randomized study to determine the effects of chemoprevention (retinoids and alpha tocopherol) on intermediate endpoints in the respiratory epithelium; 2) instituted smoking cessation study; and 3) developed new secondary prevention strategies showing that: a) NEP expression is low or absent in lung cancer and that recombinant NEP therapy inhibits lung cancer growth, b) cyclin D1 is overexpressed in new small cell lung cancer while RB is absent in SCLC and that anti-sense cyclin D1 can reverse cyclin D1 overexpression and inhibit growth; c) certain pharmacologic agents (e.g., substance P derivatives and bradykinin analogs) and mutant genes (e.g., Galpha16Q212L) induce discordant signalling in SCLC cells leading to apoptosis through activation of the JNK pathway; and d) developed intratracheal and aerosolized inhalation delivery techniques. With respect to the development of new treatment strategies, the above statements on developing prevention strategies apply and se; 1) completed a phase I study of dexnigulidipine which determined the dose for phase II studies and are nearing completion of the phase II study; 2) accrued over 100 patients to phase I studies of new therapies in advanced lung cancer showing the MTD for paclitaxel/carboplatin in NSCLC and paclitaxel/etoposide/cisplatin in SCLC demonstrating that these are among the most active regimens known. During the next 5 years, we will expand on the discoveries to date by; 1) conducting 8 inter-relating full research projects (5 continuing, 3 new); 2) initiating 4--5 pilot projects annually; 3) conducting more than 12 clinical trial; 4) supporting 5 core resources including the expanded premalignant and cancer bank; 5) supporting the career development of 2 or 3 individuals annually; and 6) supporting t he recruitment of new areas of expertise in the study of lung cancer. The materials collected in our tissue banks will continue to be made available to scientists worldwide. We will continue our collaborations with other lung cancer SPORE and lung cancer scientists to reach our goals.